We previously established a model of L. major infection combining two main features of natural transmission; inoculation of a low number of metacyclic promastigotes into the mouse ear dermis. This approach has allowed us to carefully monitor the dynamic events occurring at the site of the inoculation and in the interconnected sites of the epidermis and draining node. The model reveals two distinct phases of the infectious process that have not been previously appreciated; the first favors the multiplication of the parasite at the site and the second drives the killing of the parasite prior to the development of pathology. The first phase (parasite growth) is remarkably silent and proceeds for up to 4 weeks independent of any effect of IL-12 or IFN- gamma, as shown by the identical kinetic of early parasite growth in cytokine-deficient mice. Dermal pathology is apparent after 4-6 weeks, and is associated with cellular recruitment and parasite killing. The killing is dependent on IL-12, IFN gamma, CD40, iNOS, and CD4+ T cells, as determined by the outcome of infection in knockout and antibody- treated mice. The model also reveals a novel, required role for CD8+ cells in immunity to cutaneous leishmaniasis. The low dose, intradermal infection model has been extended to L. tropica, in which the silent phase of parasite growth appears to be prolonged for up to 3-4 months prior to the onset of control mechanisms. While the growth of the parasite is contained, there is no dermal Pathology, parasite clearance does not occur, and a transmissible level of parasitemia persists in the skin for the life of the animal. The respective outcomes of L. major and L. tropica infection following low dose intradermal challenge beautifully reproduce the clinical outcomes of these infections in disease endemic regions.Leishmania parasites are able to delay the onset of cell-mediated immunity by selectively impairing the ability of infected macrophages to produce IL-12. Leishmania infection arrests JAK/STAT mediated signal transduction involved in activation of the IL- 12p40 promoter; the phosphorylation defects may be initiated by ligation of the phagocyte receptors (CR3) used by these organisms to gain entry into the host cell.The first generation vaccines composed of whole cell, heat-killed promastigotes with or without BCG (used as adjuvant) represent materials which are presently being used in clinical trials. A new formulation of a heat killed vaccine that includes alum as an adjuvant has recently been evaluated in a Rhesus macaque model of infection. The combination of two adjuvants, BCG and alum, in an intradermal injection has not been evaluated previously. Following a single high dose (.5-1 mg) intradermal injection, all monkeys had strong induration and a smaller degree of ulceration at the vaccination site. These lesions required 3 months to resolve. All monkeys immunized with ALM/Alum/BCG were completely protected against intradermal challenge. Clinical trials of the alum adsorbed vaccine plus BCG are being planned. Second generation DNA vaccines have been extensively explored in mouse models. Protective immunity against cutaneous leishmaniasis has been demonstrated using DNA vaccines encoding three different leishmanial antigens; LACK, M15, MAPS. The DNA vaccines could be administered subcutaneously, they did not require adjuvants, and perhaps most importantly, at least in the case of LACK DNA, the immunity lasted far longer than immunization using the recombinant protein given with rIL-12 as adjuvant. Monkey trials of these DNA vaccines are planned in the coming year. - Cutaneous leishmaniasis, skin, IL-12, CD8, STAT1, dendritic cells, DNA vaccines